serena s. spudich, md, ma - ias-usa · pdf fileserena s. spudich, md ... 40 year old man with...

1

HIV Reservoirs in the Brain: Where, When, How, and What

Do They Mean for Our Patients?

FORMATTED: 10/25/2016

New York, New York: November 4, 2016

Serena S. Spudich, MD, MAProfessor of Neurology

Yale UniversityNew Haven, Connecticut

Slide 2 of 37

Serena S. Spudich, MDDepartment of Neurology

Yale University

HIV reservoirs in the brain: Where, when, how, and what do they mean for our patients?

IAS–USA New York, NYNovember 4, 2016

Slide 5 of 37

• Doing well off ART > 8 years

• No replication‐competent HIV

• Waning HIV antibodies

• No HIV‐specific T cells

‘Berlin patient’ revealed possibility of HIV cure, creating new critical question – is the brain an HIV reservoir?

Slide courtesy of Steve Deeks


2

Slide 6 of 37

How/when are HIV reservoirs established in the brain?

Do HIV reservoirs exist in the brain during cART?

How will HIV cure strategies impact the brain?

How should we consider the brain in our management of

patients?

Key questions relevant to brain reservoirs for HIV

Slide 7 of 37

Thuso: 40 year old man with difficulty walking

40 yo man presented 3/2016 with leg weakness and balance difficulty, vague cognitive symptoms, + urinary incontinence.

• Diagnosed with HIV in 2008, cART‐naïve.

• Labs: Plasma HIV RNA 1.7 million cps/ml and CD4 31 cells/ul.

• CSF microbiology all negative, except CSF HIV RNA >10 million cps/ml.

• MRI Brain (FLAIR sequence) shown below with atrophy and diffuse subcortical white matter changes.

Slide 8 of 37

Diagnosis: HIV‐associated dementia.

Days post ART initiation

0 50 100 150 200 2501

2

3

HIV

RNA (lo

0 50 100 150 200 250-10

-8

-6

-4

-2

0

2

QNZP-4

0 50 100 150 200 2500

20

40

60

DSY

Days

Dig

it Sym

bol (

DSY)

• How does this CNS impact change with potent ART? Do reservoirs for HIV exist within the brain in most patients?

• Since the beginning of the epidemic, CNS involvement has been a hallmark of HIV.

• In some individuals, HIV particularly manifests as CNS dysfunction with profound CNS HIV replication.

QNPZ‐4 – summarized neurologic performance

Thuso: 40 year old man with difficulty walking


3

Slide 9 of 37

HIV‐ tat

Blood brain barrier breakdown

Neurotoxic products (free radicals, cytokines)

HIV‐1 proteins (gp120, tat)

NeopterinChemokines (IP‐10, MCP‐1)

Blood

Brain

Mechanisms of CNS HIV infection prior to ART

Slide 10 of 37





patients?


Slide 11 of 37

Garvey et al, AIDS. 2014; Anthony et al, J Neuropath ExpNeur, 2005; Dahl et al, AIDS 2014.

Positron emission tomography (PET): Abnormal brain uptake of ligand specific for activated microglial cells (>3 years of ART vs HIV‐).

Brain autopsy: Increased activated microglia (CD68+ cells) in (> 1.5 years ART vs HIV‐).

Persistent macrophage/microglial activation on cART with plasma viral suppression

CSF: Elevated CSF neopterin, marker of macrophage activation, associates with detectable CSF HIV RNA by single copy assay (> 10 years of ART).

/ HIV‐


4

Slide 12 of 37

HIV DNA detected in brain on ART with plasma viral suppression (sudden death)

Slide and data courtesy of Joe Wong

HIV RNA seldom measurable in brain

Wong, Yukl, et al, Keystone HIV Persistence Conference, April 2015

Patient ID Sample type /cell # # +ve PCR reactions Sequence

determined # Unique sequences

GPDH V3

T82 1 0/5 0/5 N -

10 4/5 0/4 N -

50 4/5 0/4 N -

1000 5/5 0/5 N -

>3000 5/5 2/5 Y 1

Slabs 5/5 3/5 Y 3

T82 PBMC - - 1 1

CT R PNNN T RK S I H I - - GPGR A F Y T T GE I I G D I RQAH C. . . . . . . . . . . . N . - - . . . . . L . . . . . . . . . . . . . . .. . . . . . . . . . R . R . QR . . . . . . V . I . K . - . NM . . . . .. . . . . . . . . . . . . . - - . . . . . . . . . . D . . . . . . . . . .. . . . S . . . . . . . . . - - . . . . . . . . . . . . . . . . . . . . .. R . - . . . . . . . . . . - - . R . . . . . . R . . . . . . . . . . . .. R . . . . - . . . . . . . - - . . . . . . . . . . D . . . . . . . . . .. R . - . . . . . . . . . . - - . R . . . . . . R . . . . . . . . E . . .. . . . . . - . . . . . . . - - . . . . . . . . . . D . . . . . . . . . .. I . . . . . . . . . . P . - - . . R . . . . . . E . . . . . . . . . . .. . . . D . . S . . . . . . - - . . . . S . FA . . D V . . . . . . . . .. . . . D . . . . . . . . . - - . . . . S . . A . . D V . . . . . . . . .. I . . . . . . . . . . R . - - . . . Q T . . A . . D . V . . . . . . Y .. . . . . . . . . . . . . . - - . . . . SC . A . . V V . . . . . . P . R

HIV DNA detected in brain on ART with plasma viral suppression

Churchill, et al, Keystone HIV Persistence Conference, April 2015Slide and data courtesy of Melissa Churchill

Slide 13 of 37

Slide 14 of 37

LamivudineAbacavirLopinavir/r

hand tremor, ataxia, slurred speech, aphasia

Latest CD4 308 cells/ul; nadir CD4 60 cells/ul

Peluso et al., AIDS, 2012.

Persistent CNS HIV replication on ART with plasma viral suppression: CNS‘escape’


5

Slide 15 of 37

CSF HIV RNA

CSF WBC = 26 cells/ul

Peluso et al., AIDS, 2012.


Slide 16 of 37

PI: I13V, K20R, M36I, I54V, L63P, V82A

RT: M41L, E44D, D67N, V118I, M184V, L210W, T215Y

Zidovudine Possible ResistanceDidanosine ResistanceLamivudine ResistanceStavudine Possible ResistanceAbacavir ResistanceTenofovir Resistance

Nevirapine No Evidence of ResistanceDelavirdine No Evidence of ResistanceEfavirenz No Evidence of Resistance

Saquinavir ResistanceIndinavir ResistanceRitonavir ResistanceNelfinavir ResistanceAmprenavir ResistanceLopinavir/r Possible ResistanceAtazanavir Possible Resistance

AbacavirLamivudine Darunavir/r NevirapineZidovudine

Resolution of signs and symptomsPeluso et al., AIDS, 2012.


Slide 17 of 37

THINC Subject 2:CSF escape at two time intervals

●

●

●

●● ● ●

● ● ● ●●

●●

2

3

4

5

6

0 10 20 30Months on HAARTLo

g H

IV v

iral l

oad

(RN

A c

opie

s/

Started DRV/ r/ TDF/ FTC

3 years after diagnosis

Log H

IV v

iral

load

(RN

A c

p/m

l)

Blood plasma

CSF

Pre-HAART T1 T2

UNC ‐ Joseph et al., THINC study


0

5

10

15

Ba−L JRCSF D12 E9 F10 A11

Per

cen

t In

fect

ivit

y a

t L

ow

CD

4

Elevated macrophage tropism of CSF escape population


6

Slide 18 of 37

Jake: Young man with recent infection, hesitant to start ART• 29 yo man diagnosed in May, 2013, probable acute HIV syndrome in Oct

2012.– On no meds, works as an electrical engineer; lives alone and has good

support network.– He wants to avoid treatment as long as possible.

6/2013 7/2013 9/2013

CD4 count 468 505 422

CD4 % 35 37 33

HIV‐1 RNA 3200 9570 16760

Slide 19 of 37





patients?


Early HIV infection studies

Slide 20 of 37

HIV RNA Levels

0 30 60 90 120 150 180 210 240 270 300 330 360

1

2

3

4

5

6

7

8

log 1

0 c

opie

s/m

l

Days Post HIV Transmission

Plasma

HIV traffics into the CNS in early infection


7

Slide 21 of 37

HIV RNA Levels

0 30 60 90 120 150 180 210 240 270 300 330 360

1

2

3

4

5

6

7

8

log 1

0 c

opie

s/m

l


Plasma CSF


Slide 22 of 37

HIV RNA Levels

0 30 60 90 120 150 180 210 240 270 300 330 360

1

2

3

4

5

6

7

8

log 1

0 c

opie

s/m

l


CSF


Slide 23 of 37

CSF Neopterin

0 30 60 90 120 150 180 210 240 270 300 330 3600

20

40

60

80

100

nm

ol/L


Neopterin, biomarker of macrophage activation, is elevated in the CNS compared to HIV negative (dotted line) throughout early infection.

Macrophage activation in the CNS is triggered in early infection


8

Slide 24 of 37

Peluso et al., JID 2013

• Neurofilament Light Chain (NFL) – specific CSF biomarker of axonal injury

Neuronal injury begins during early infection

CSF NFL

0

1000

2000

3000

ng/L

HIV- AHI PHI CHI

Slide 25 of 37

HIV RNA Levels

0 30 60 90 120 150 180 210 240 270 300 330 360

1

2

3

4

5

6

7

8

log 1

0 c

opie

s/m

l


CSF

Slide 26 of 37

0-4 months(n=44)

5-12 months(n=70)

68% 61%14%

16%

2%

13%

6%

7%

13%

A

Not Analyzed Equilibrated (-) Equilibrated (+) Intermediate Compartmentalized

Variable compartmentalization of env sequences between plasma and CSF in primary infection

Sturdevant C., PloS Pathogens 2015

BloodCSF


9

Slide 27 of 37

Slide 28 of 37





patients?


Slide 29 of 37Plasma HIV RNA

0 20 40 60 80 100 120 1401

2

3

4

5

6

7

HIV

RNA (lo

g10

cps/m

l)

CSF HIV RNA

0 20 40 60 80 100 120 1401

2

3

4

5

6

7

HIV

RN

A (l

og

10 c

ps/m

l)

CSF WBCs

0 20 40 60 80 100 120 140

0

10

20

30

40

50

60

Days

cells

/L

CSF HIV and CNS inflammation after ART interruption

Price, Deeks, J Neurovirology 2004.


10

Slide 30 of 37

• CSF: inflammatory markers, virology, injury markers• Neuroimaging: MRS, volumetrics, DTI & rs‐fMRI at 3 Tesla magnet strength• Clinical: Neurological exams & neuropsychological assessments

How will HIV cure strategies affect the CNS?

Pre‐ART On ART During intervention/before ATI

At plasma rebound (or before)

On ART in follow up protocol

ART

‘cure’ intervention

ART Interruption

ART

Collaborators: V. Valcour, J. Ananworanich

Slide 31 of 37

SEARCH 026: HIV ‘cure’ intervention with HDAC‐inhibitor, followed by treatment interruption

Wk 0

Start VHM

Wk 10

Stop VHM, Begin ART interrup9on

F/u on ART LP/MRI/NP LP/NP

Detectable plasma HIV

RNA LP/NP MRI/NP

Resume ART

Kroon, et al., IAS Cure Symposium & IAS, 2016

Slide 32 of 37


VHM: Vorinostat (HDAC‐inhibitor)+ Hydroxychloroquine + Maraviroc

SEARCH 026: HIV ‘cure’ intervention with HDAC‐inhibitor,followed by treatment interruption

A. Plasma HIV RNA

Baseline Wk10 VHM ATI On ART

0

10000

20000

30000

40000

HIV

RN

A (c

ps/m

L)

B. CSF HIV RNA Standard Assay

Baseline Wk10 VHM ATI10

20

30

40

50

HIV

RN

A (cps/m

L)

C. CSF HIV RNA Single Copy Assay

Baseline Wk10 VHM ATI0

1

2

3

4

5

20

30

40

50

HIV

RN

A (c

ps/m

L)


11

Slide 33 of 37


VHM: Vorinostat (HDAC‐inibitor)+ Hydroxychloroquine + Maraviroc

A. CSF Protein

Baseline Wk10 VHM ATI

10

20

30

40

50

60

Pro

tein

(mg/d

L)

B. CSF IP-10/CXCL10


0

50

100

150

200

IP-1

0/C

XC

L10 (pg/m

l)

p = 0.017

C. CSF MCP-1/CCL-2


0

500

1000

1500

MC

P-1

/CC

L-2

(pg/m

l)

D. CSF Neopterin


0

2

4

6

CSF N

eopte

rin (n

mol/L

)

SEARCH 026: HIV ‘cure’ intervention with HDAC‐inhibitor, followed by treatment interruption

Slide 34 of 37





patients?


ACTG A5324: Effects of ART intensification on the brain

• Weill Cornell Uptown SiteE 68th St at York AvenueValery Hughes, FNP

212‐746‐4393

• Weill Cornell Chelsea SiteW 23rd St between 5th and 6th

Todd Stroberg, RN212‐746‐7198

• Randomized, placebo‐controlled, double‐blinded phase IV clinical trial, 96 weeks• Study Population (n=186; arms=62)

– Mild neurocognitive impairment (includes neuroasymptomatic)– On stable ART treatment >1 year– Plasma HIV‐1 RNA less than 50 copies/mL

Study Regimens– A: No intensification – B: Intensification with DTG– C: Intensification with DTG and MVC

Slide 35 of 37


12

Slide 36 of 37

2016 USA HIV treatment guidelines (http://aidsinfo.nih.gov/guidelines)

Treat all individuals at the time of HIV diagnosis.

HIV guidelines now incorporate CNS considerations:

• Due to CNS toxicities, efavirenz no longer in first‐line recommended regimens.

• Treatment recommendations for HIV Associated Dementia (no efavirenz, favor regimens with higher presumed CNS penetration).

• Evaluation/treatment of ‘symptomatic CNS escape’ including lumbar puncture for CSF viral load, CSF drug resistance testing and consideration of CNS penetration.

Clinical management of HIV and the brain in 2016

Slide 37 of 37

UNC:Ron SwanstromSarah JosephChrista SturdevantGretja SchnellKevin RobertsonJoe EronTHINC team

U. Gothenburg:Lars HagbergMagnus GisslenHenrik Zetterberg

Milan: Paola Cinque

Sydney:Bruce BrewSarah PalmerInnsbruck: Dietmar Fuchs

AcknowledgementsYale:Michael KozalBrinda EmuLeah LeJen ChiarellaBarbara TurcotteLaurie AndrewsSebastian UrdayMichael PelusoAndrew YoungJoome SuhIdil KoreElham RahimyAndrew SilvermanTess O’Meara

UCSF/San Francisco:

Victor ValcourJoanna HellmuthCollin AdamsLauren WendelkenRichard W. Price Evelyn LeeJulia PetersonRick HechtChris PilcherUCSF Options Study Magnet StaffTeri Liegler

Study Participants

WRAIR/MHRPJintanat AnanworanichSodsai TovanabutraGustavo KijakSuteeraporn PinyakornNelson MichaelJerome KimMerlin Robb

Thai Red Cross AIDS Res Center/SEARCHNittaya PhanuphakPraphan PhanuphakMark de SouzaFrits van GriensvenJames FletcherEugene KroonDonn ColbyCarlo Nitiya ChomcheyDuanghathai SuttichomSomprartthana RattanamaneePeeraya MunguPutthachard SaengtawanTippawan Pankam

Study Participants

NIHR21MH110260R21MH099979R01MH081772R01MH095613R01 NS084911K23MH074466W81XWH‐11‐2‐0174; IAA number NIAID Y1‐AI502602US Military HIV Research Program

Funding Support


serena s. spudich, md, ma - ias-usa · pdf fileserena s. spudich, md ... 40 year old man with...

Documents